Acne Inversa, Familial, 2, With Or Without Dowling-Degos Disease

A number sign (#) is used with this entry because acne inversa-2 with or without Dowling-Degos disease (ACNINV2) is caused by heterozygous mutation in the PSENEN gene (607632) on chromosome 19q13.

Description

Acne inversa is a chronic inflammatory disease of the hair follicles whose characteristic features include draining sinuses, painful skin abscesses, and disfiguring scars. Manifestations typically appear after puberty. Familial acne inversa is genetically heterogeneous (summary by Wang et al., 2010). Some patients with PSENEN-associated acne inversa also exhibit reticulate hyperpigmentation consistent with Dowling-Degos disease (DDD; see 179850) (Zhou et al., 2016).

For a general phenotypic description and a discussion of genetic heterogeneity of acne inversa, see 142690.

Clinical Features

Wang et al. (2010) reported 2 unrelated Han Chinese families with acne inversa: family 1 with 11 patients over 4 generations, and family 2 with 19 patients over 4 generations. Affected individuals showed lesions in typical areas, including the axillae, groin, and perianal, perineal, inframammary, and buttock regions. In addition, there were lesions in atypical areas such as the face, nape of neck, back, waist, and hip. The proband of family 1 also had squamous cell carcinoma in the left axilla. Li et al. (2017) restudied these families and stated that 4 of the 11 patients from family 1 showed manifestations consistent with Dowling-Degos disease.

Pink et al. (2011) described a mother and daughter with hidradenitis suppurativa, who both developed boils and abscesses in the axillae, under the breasts, and in the groin at 15 years of age. The daughter was more severely affected and had additional lesions over her buttocks with scarring and sinus tract formation. Examination of mother and daughter revealed mild macular hyperpigmentation in the axillae and groin areas. The mother had a body mass index in the 'obese' range, whereas the daughter was of normal weight; neither had ever smoked.

Zhou et al. (2016) studied 2 unrelated 4-generation Chinese families in which affected individuals exhibited extensive comedones and pitted scars on the face, neck, and trunk, as well as reticulate pigmentation in the flexural areas. Age of onset was 15 to 18 years in all patients. Skin biopsy from the proband of family 1 showed dilated hair follicles with follicular plugging and perifollicular acanthosis, with downward elongation of rete ridges in a reticulated pattern and a few horn cysts. The authors noted that the pathologic changes were similar to those reported in Dowling-Degos disease. The brother of the proband from family 1 was severely affected with abscesses, cysts, and scars, and he developed a well-differentiated squamous cell carcinoma in the anal canal at age 38 years. The tumor was removed, but 2 years later he developed metastases to lymph nodes and bone.

Ralser et al. (2017) studied 10 patients from 6 families diagnosed with Dowling-Degos disease who were negative for mutations in DDD-associated genes but had mutations in the PSENEN gene. Review of histologic sections from the patients revealed follicular hyperkeratosis, which the authors noted had not previously been reported in DDD cases. Acne inversa was present in 6 of the patients, all of whom reported nicotine use and/or obesity.

Li et al. (2017) reported a large 4-generation Chinese family with acne inversa and a mutation in the PSENEN gene that segregated with the disease. Of the 21 affected individuals, only 1 showed typical manifestations of DDD, with reticulate hyperpigmentation in the axillae, groin, and perineal region; 2 additional patients had mild macular pigmentation of the neck. Some of the older patients exhibited follicular papules, comedones, noninflammatory nodules, and scattered atrophic scars on their axillae, perianal area, and nape of neck. The authors noted that the findings in the latter patients did not fully meet the diagnostic criteria for acne inversa, and suggested that some PSENEN mutation carriers with mild acne inversa might be misdiagnosed.

Molecular Genetics

Wang et al. (2010) mapped an acne inversa locus to an interval on chromosome 19q13 using 2 large 4-generation Han Chinese families. Each family had a frameshift mutation in the PSENEN gene (607632.0001, 607632.0002).

Pink et al. (2011) screened 7 families with hidradenitis suppurativa for mutations in 3 acne inversa-associated genes and identified heterozygosity for a 1-bp insertion in the PSENEN gene (607632.0003) in an affected mother and daughter.

In 2 unrelated 4-generation Chinese families with acne inversa and Dowling-Degos disease, Zhou et al. (2016) sequenced 3 acne inversa-associated genes and identified heterozygosity for mutations in the PSENEN gene: a missense mutation in family 1 (L65R; 607632.0004) and a splice site mutation in family 2 (607632.0005). The mutations segregated with disease in each family, and neither mutation was found in 100 ethnically matched controls.

In 10 patients from 6 unrelated families diagnosed with Dowling-Degos disease, of whom all were negative for mutation in DDD-associated genes and 6 also exhibited acne inversa, Ralser et al. (2017) performed exome sequencing and identified heterozygous mutations in the PSENEN gene (see, e.g., 607632.0006 and 607632.0007) that segregated with disease in each family and were not found in public variant databases. Noting that all 6 patients with acne inversa reported nicotine use and/or obesity, the authors hypothesized that PSENEN mutation carriers present primarily with DDD, whereas those with a history of nicotine use or obesity have an increased susceptibility to comorbid acne inversa.

Li et al. (2017) reviewed 11 previously reported families (Wang et al., 2010; Pink et al., 2011; Zhou et al., 2016; Ralser et al., 2017) and 1 unpublished Chinese family with PSENEN-associated acne inversa and/or DDD, and also reported an additional large 4-generation Chinese pedigree ('family 5') with acne inversa and the L65R mutation (607632.0004) in the PSENEN gene. Li et al. (2017) observed intrafamilial variability in severity of lesions, which they suggested might be due to reduced penetrance involving different genetic and environmental factors. Noting that more than half of the patients from the 13 families showed only acne inversa and a minority showed acne inversa with comorbid DDD, the authors proposed that the comanifestation of acne inversa and DDD represents a subtype of acne inversa in some PSENEN mutation carriers.